The immediate objective of this application is to provide high level pre-doctoral research training to Mr. Daniel Miller. Head and neck squamous cell carcinoma (HNSCC) is the 6th most commonly diagnosed cancer worldwide, with a half-million annual diagnoses, >200,000 deaths annually, and US deaths occurring at a rate of 1 death/hour. Molecular studies have revealed that 40-80% of oropharyngeal squamous cell carcinomas (OPSCC) diagnosed in the US contain human papilloma virus (HPV). The incidence of OPSCC has increased significantly at a rate of 1.3% and 0.6% yearly between 1973 and 2004 for base of tongue and tonsillar carcinomas, respectively. Although epidemiological and molecular studies support HPV+ OPSCC as a distinct clinical entity, the pathobiology of HPV-associated OPSCC initiation and progression is poorly understood. A more detailed understanding of molecular events associated with HPV+ OPSCC progression is therefore a prerequisite for improved staging and diagnostic/prognostic stratification. MicroRNAs (miRNA) are small non-coding RNAs that participate in post-transcriptional gene silencing by regulating mRNA translation, thereby significantly altering the protein output of a cell. Unlike many DNA viruses that express their own miRNAs, papillomaviruses instead alter the expression of cellular miRNAs;however the relationship between HPV status and miRNA profiles in OPSCC has not been evaluated. To address this significant gap, the current proposal will test the hypothesis that HPV+ OPSCC lesions display distinct miRNA profiles and that alterations in specific miRNAs contribute to disease progression. To investigate this hypothesis, we will conduct microRNA profiling of HPV+ and HPV- OPSCC tumors, perform functional analysis of miRNA-modified cells, and generate transcriptomic and proteomic profiles of miRNA-modified OPSCC. The completed project will provide important insight into the disease entities of HPV+ and HPV- OPSCC with potential to improve diagnostic and therapeutic strategies. PUBLIC HEALTH RELEVANCE: Oral cavity cancer ranks among the top ten most frequently diagnosed cancers worldwide, resulting in over 200,000 deaths annually, but the 5-year survival rate has remained at a low 50% for the past 20 years, indicating that new approaches to target OSCC are urgently needed. Emerging evidence highlights human papillomavirus (HPV) as a potential causative agent in some forms of oral cancer. The immediate objective of these studies is to provide high quality PhD research training to Mr. Daniel Miller. The proposed research will use new technologies, including transcriptomics, proteomics, bioinformatics, and novel imaging techniques, to discover the role of microRNAs in controlling the formation, growth and spread of HPV+ OSCC.